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Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial

22 Pages Posted: 11 Nov 2020

See all articles by Alejandro Krolewiecki

Alejandro Krolewiecki

Universidad Nacional de Salta - Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET)

Adrián Lifschitz

National University of Central Buenos Aires - Laboratorio de Farmacología

Matías Moragas

CONICET - Unidad de Virología y Epidemiología Molecular

Marina Travacio

University of Buenos Aires (UBA) - Cátedra de Química General e Inorgánica

Ricardo Valentini

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) - Departamento de Medicina

Daniel F. Alonso

Universidad Nacional de Quilmes - Centro de Oncología Molecular y Traslacional (COMTra) y Plataforma de Servicios Biotecnológicos

Rubén Solari

Hospital Francisco J. Muñiz

Marcelo Adrián Tinelli

Laboratorio Elea/Phoenix

Rubén O. Cimino

Universidad Nacional de Salta - Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET)

Luis Álvarez

National University of Central Buenos Aires - Laboratorio de Farmacología

Pedro Emanuel Fleitas

Universidad Nacional de Salta - Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET)

Laura Ceballos

National University of Central Buenos Aires - Laboratorio de Farmacología

Marcelo Darío Golemba

CONICET - Unidad de Virología y Epidemiología Molecular

Florencia Fernández

CONICET - Unidad de Virología y Epidemiología Molecular

Diego Fernández de Oliveira

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) - Departamento de Medicina

Germán Astudillo

Hospital Francisco J. Muñiz

Inés Baeck

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) - Departamento de Medicina

Javier Farina

Hospital Cuenca Alta - Servicio de Infectología

Marcelo David Guthmann

Universidad Nacional de Quilmes - Centro de Oncología Molecular y Traslacional (COMTra) y Plataforma de Servicios Biotecnológicos

Georgina A. Cardama

Universidad Nacional de Quilmes - Centro de Oncología Molecular y Traslacional (COMTra) y Plataforma de Servicios Biotecnológicos

Andrea Mangano

CONICET - Unidad de Virología y Epidemiología Molecular

Eduardo Spitzer

Laboratorio Elea/Phoenix

Silvia Gold

Fundación Mundo Sano

Carlos Lanusse

National University of Central Buenos Aires - Laboratorio de Farmacología

More...

Abstract

Background: There are limited antiviral options for the treatment of patients with coronavirus disease 2019 (COVID-19) that have demonstrated clinical efficacy and none of them is an oral drug. Ivermectin (IVM), a macrocytic lactone with a wide anti-parasitary spectrum, has shown potent in vitro activity against SARS-CoV-2 in cell cultures. 

Methods: We completed a pilot, randomized, controlled, outcome-assessor blinded clinical trial with the goal of evaluating the antiviral activity of high dose IVM in COVID-19 patients. Eligible patients were adults (aged 18 to 69 years) with mild or moderate RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. 45 patients were randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care. The primary endpoint was viral load reduction in respiratory secretions at day-5. Viral load in respiratory secretions was measured through quantitative RT-PCR. Concentrations of IVM in plasma were measured on multiple treatment days.

Findings: The trial run between May 18 and September 29, 2020 with 45 randomized patients (30 in the IVM group and 15 controls). There was no difference in viral load reduction between groups but a significant difference in reduction was found in patients with higher median plasma IVM levels (72% IQR 59 – 77) versus untreated controls (42% IQR 31 – 73) (p=0·004). The mean ivermectin plasma concentration levels also showed a positive correlation with viral decay rate (r:0·47, p=0·02). Adverse events were reported in 5 (33%) patients in the controls and 13 (43%) in the IVM treated group, without a relationship between IVM plasma levels and adverse events.

Interpretation: A concentration dependent antiviral activity of oral high dose IVM was identified in this pilot trial at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.

Trial Registration: This trial is registered with ClinicalTrials.gov, NCT004381884.

Funding Statement: This work was supported by grant IP-COVID-19-625 from Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

Declaration of Interests: AK reports grants from Laboratorio Elea/Phoenix. MAT, MDG and ES are employees of Laboratorios Elea/Phoenix. SG is a moember of the Board of Directors of Laboratorio Elea/Phoenix. All other authors declare no competing interests.

Ethics Approval Statement: Ethical approval was obtained from the Institutional Independent Ethics Committees and from district and national regulatory agencies. All participating individuals provided written informed consent. The trial was done in accordance with the principles of the Declaration of Helsinki.

Keywords: Covid-19, Ivermectin, SARS-CoV-2, antivirals, viral decay rate

Suggested Citation

Krolewiecki, Alejandro and Lifschitz, Adrián and Moragas, Matías and Travacio, Marina and Valentini, Ricardo and Alonso, Daniel F. and Solari, Rubén and Tinelli, Marcelo Adrián and Cimino, Rubén Oscar and Álvarez, Luis and Fleitas, Pedro Emanuel and Ceballos, Laura and Golemba, Marcelo Darío and Fernández, Florencia and Fernández de Oliveira, Diego and Astudillo, Germán and Baeck, Inés and Farina, Javier and Guthmann, Marcelo David and Cardama, Georgina A. and Mangano, Andrea and Spitzer, Eduardo and Gold, Silvia and Lanusse, Carlos, Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial. Available at SSRN: https://ssrn.com/abstract=3714649 or http://dx.doi.org/10.2139/ssrn.3714649

Alejandro Krolewiecki (Contact Author)

Universidad Nacional de Salta - Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET) ( email )

Argentina

Adrián Lifschitz

National University of Central Buenos Aires - Laboratorio de Farmacología ( email )

Gral. Pinto 399
Buenos Aires, Tandil B7000GHG
Argentina

Matías Moragas

CONICET - Unidad de Virología y Epidemiología Molecular ( email )

Buenos Aires, C1425FQB
Argentina

Marina Travacio

University of Buenos Aires (UBA) - Cátedra de Química General e Inorgánica ( email )

Av. Cordoba 2122
Buenos Aires, Buenos Aires 1120
Argentina

Ricardo Valentini

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) - Departamento de Medicina ( email )

Las Heras 2981
Buenos Aires
Argentina
005452990600 (Phone)

Daniel F. Alonso

Universidad Nacional de Quilmes - Centro de Oncología Molecular y Traslacional (COMTra) y Plataforma de Servicios Biotecnológicos

Buenos Aires
Argentina

Rubén Solari

Hospital Francisco J. Muñiz ( email )

Marcelo Adrián Tinelli

Laboratorio Elea/Phoenix ( email )

Rubén Oscar Cimino

Universidad Nacional de Salta - Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET) ( email )

Argentina

Luis Álvarez

National University of Central Buenos Aires - Laboratorio de Farmacología

Gral. Pinto 399
Buenos Aires, Tandil B7000GHG
Argentina

Pedro Emanuel Fleitas

Universidad Nacional de Salta - Instituto de Investigaciones de Enfermedades Tropicales (IIET-CONICET) ( email )

Argentina

Laura Ceballos

National University of Central Buenos Aires - Laboratorio de Farmacología ( email )

Gral. Pinto 399
Buenos Aires, Tandil B7000GHG
Argentina

Marcelo Darío Golemba

CONICET - Unidad de Virología y Epidemiología Molecular ( email )

Buenos Aires, C1425FQB
Argentina

Florencia Fernández

CONICET - Unidad de Virología y Epidemiología Molecular ( email )

Buenos Aires, C1425FQB
Argentina

Diego Fernández de Oliveira

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) - Departamento de Medicina ( email )

Argentina

Germán Astudillo

Hospital Francisco J. Muñiz ( email )

Inés Baeck

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) - Departamento de Medicina ( email )

Argentina

Javier Farina

Hospital Cuenca Alta - Servicio de Infectología ( email )

Marcelo David Guthmann

Universidad Nacional de Quilmes - Centro de Oncología Molecular y Traslacional (COMTra) y Plataforma de Servicios Biotecnológicos ( email )

Buenos Aires
Argentina

Georgina A. Cardama

Universidad Nacional de Quilmes - Centro de Oncología Molecular y Traslacional (COMTra) y Plataforma de Servicios Biotecnológicos ( email )

Buenos Aires
Argentina

Andrea Mangano

CONICET - Unidad de Virología y Epidemiología Molecular ( email )

Buenos Aires, C1425FQB
Argentina

Eduardo Spitzer

Laboratorio Elea/Phoenix

Silvia Gold

Fundación Mundo Sano ( email )

Carlos Lanusse

National University of Central Buenos Aires - Laboratorio de Farmacología ( email )

Gral. Pinto 399
Buenos Aires, Tandil B7000GHG
Argentina

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